Amyotrophic lateral sclerosis (ALS) results from the progressive degeneration of motor neurons. Astrocytes are important for neuronal function and survival, but exactly how astrocytes contribute to ALS pathogenesis is not known. Compared to neurons, astrocytes can be replaced much more easily and thus are the focus of regenerative medicine. Familial ALS is caused by pathogenic mutation in individual genes, including TDP-43. A critical need in ALS research is determining how astrocytes contribute to the initiation and progression of motor neuron degeneration in the presence and absence of the disease gene in astrocytes. Using a tetracycline- inducible gene expression system, we have created transgenic rats that restrictedly and reversibly express mutant TDP-43 in astrocytes. By microarray assays, we have determined the expression profiles of astrocytic genes. Many secretory genes are induced in astrocytes expressing mutant TDP-43. Functional analyses of astrocytic genes suggest a loss of neuroprotective functions and a gain of neurotoxic properties in astrocytes expressing mutant TDP-43. Here we will further determine how mutant TDP-43 in astrocytes causes non-cell- autonomous motor neuron death in transgenic rats. In response to neurodegeneration, astrocytes become reactive and may play important roles in disease pathogenesis. Increasing evidence strongly suggests that reactive astrocytes gain neurotoxic properties, but how reactive astrocytes execute neurotoxicity remains to be determined. Using various approaches, we have identified an inducible gene that is secreted by reactivate astrocytes. We will further define the route by which reactive astrocytes use to promote neurodegeneration. This proposal will determine how astrocytes contribute to the initiation and progression of motor neuron death in the presence and absence of mutant TDP-43 in astrocytes, advancing our understanding of ALS disease mechanisms.